Paradoxical Impact of Two Folate Receptors, FRa and RFC, in Ovarian Cancer: Effect on Cell Proliferation, Invasion and Clinical Outcome

Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRa) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRa and RFC in ovarian cancers. We demonstrated FRa mRNA and protein overexpression and reduced RFC expression in association with FRa gene amplification and RFC promoter hypermethylation, respectively. FRa overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRa or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRa and confer a protective effect in patients with high FRa-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRa (putative oncogenic) and RFC (putative tumor suppressive) i